US9315468B2 - Methods including latent 1,3-dipole-functional compounds and materials prepared thereby - Google Patents

Methods including latent 1,3-dipole-functional compounds and materials prepared thereby Download PDF

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US9315468B2
US9315468B2 US13/876,024 US201113876024A US9315468B2 US 9315468 B2 US9315468 B2 US 9315468B2 US 201113876024 A US201113876024 A US 201113876024A US 9315468 B2 US9315468 B2 US 9315468B2
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cyclic alkyne
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Geert-Jan Boons
Frederic Friscourt
Petr A. Ledin
Ngalle Eric Mbua
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University of Georgia Research Foundation Inc UGARF
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention was made with government support by the National Cancer Institute of the U.S. National Institutes of Health (R01 CA88986, G.-J.B.), the National Science Foundation Plant Genome Program (IOS-0923992, G.-J.B.), and the National Science Foundation (CHE-0449478, V.V.P.). The Government has certain rights in this invention.
  • the present disclosure provides a method of preparing a heterocyclic compound and the heterocyclic compounds prepared thereby.
  • the method includes: providing at least one latent 1,3-dipole-functional compound; converting the at least one latent 1,3-dipole-functional compound into at least one active 1,3-dipole functional compound; contacting the at least one active 1,3-dipole functional compound with at least one cyclic alkyne; and allowing the at least one active 1,3-dipole-functional compound and the at least one cyclic alkyne to react under conditions effective for a cycloaddition reaction (e.g., a [3+2] dipolar cycloaddition reaction) to form the heterocyclic compound, preferably in the substantial absence of added catalyst.
  • converting the at least one latent 1,3-dipole-functional compound into the at least one active 1,3-dipole functional compound is performed in the presence of the at least one cyclic alkyne.
  • the present disclosure provides a method of preparing compounds having one or more heterocyclic groups and the compound prepared thereby.
  • the method includes: combining components including a first component having a first 1,3-dipole-functional group (e.g., an azide group), a second component having a latent 1,3-dipole-functional group that can be converted into a second active 1,3-dipole functional group that is different than the first 1,3-dipole functional group, and a cyclic alkyne; allowing the first component having the first 1,3-dipole-functional group to react with the cyclic alkyne under conditions effective for a cycloaddition reaction (e.g., a [3+2] dipolar cycloaddition reaction) to form a first heterocyclic group; converting the latent 1,3-dipole-functional group of the second component into the second active 1,3-dipole functional group; and allowing the second component having the second active 1,3-dipole-functional group
  • the one or more latent 1,3-dipole-functional compounds and/or groups can be an oxime, and converting the one or more latent 1,3-dipole-functional compounds and/or groups into the one or more active 1,3-dipole functional compounds and/or groups can include converting the oxime into a nitrile oxide.
  • a wide variety of methods can be used for converting the oxime into a nitrile oxide.
  • suitable methods for converting the oxime into a nitrile oxide include direct oxidation using a mild oxidant such as, for example, [bis(acetoxy)iodo]benzene (BAIB).
  • the one or more latent 1,3-dipole-functional compounds and/or groups can be an imidoyl chloride, and converting the one or more latent 1,3-dipole-functional compounds and/or groups into the one or more active 1,3-dipole functional compounds and/or groups can include converting the imidoyl chloride into a nitrile oxide.
  • a wide variety of methods can be used for converting the imidoyl chloride into a nitrile oxide.
  • suitable methods for converting the imidoyl chloride into a nitrile oxide include, for example, treatment with a mild base.
  • cyclic alkynes can be used in the methods disclosed herein including, but not limited to, cyclooctynes, monoarylcyclooctynes, and diarylcyclooctynes.
  • diarylcyclooctynes include dibenzocyclooctynes of the formula:
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group
  • X represents C ⁇ O, C ⁇ N—OR 3 , C ⁇ N—NR 3 R 4 , CHOR 3 , CHNHR 3 , BR 3 , NR 3 , O, SiR 3 R 4 , PR 3 , O ⁇ PR 3 or halogen
  • each R 3 and R 4 independently represents hydrogen or an organic group.
  • Preferred cyclic alkynes include those of Formula I wherein each R 1 represents hydrogen, each R 2 represents hydrogen; X represents CHOR 3 , and R 3 is selected from the group consisting of an alkyl group, an aryl group, an alkaryl group, and an aralkyl group.
  • diarylcyclooctynes include aza-dibenzocyclooctynes of the formula:
  • each R 1 independently represents H or an organic group
  • R 2 represents a —C(O)—R 4 group
  • R 4 represents an organic group.
  • each R 1 is hydrogen.
  • diarylcyclooctynes include aza-dibenzocyclooctynones of the formula:
  • each R 1 independently represents H or an organic group
  • R 2 represents an organic group.
  • each R 1 is hydrogen.
  • Exemplary cyclooctynes include difluorinated cyclooctynes of the formula:
  • R 1 represents an organic group
  • the methods disclosed herein can optionally include one or more reactions that take place within or on the surface of a living cell.
  • at least one 1,3-dipole-functional compound and/or group includes a 1,3-dipole-functionalized biomolecule and/or a detectable label (e.g., an affinity label) that can enable detecting at least one formed heterocyclic compound using, for example, affinity binding.
  • a detectable label e.g., an affinity label
  • the methods disclosed herein can be used to prepare articles that include, for example, a functionalized substrate surface.
  • FIG. 1 illustrates structures for exemplary embodiments of cyclooctynes.
  • FIG. 2 illustrates structures for exemplary embodiments of monoarylcyclooctynes (e.g., monobenzocyclooctynes).
  • FIG. 3 illustrates structures for exemplary embodiments of diarylcyclooctynes (e.g., dibenzocyclooctynes).
  • FIG. 4 illustrates exemplary cyclooctynes that can be used for dipolar cycloaddition reactions for certain embodiments of the methods disclosed herein.
  • FIG. 5 illustrates exemplary cycloaddition reactions of 4-dibenzocyclooctynol (DIBO, 2) with various 1,3-dipoles and the rate constants for the reactions.
  • the 1,3-dipoles illustrated include nitrile oxide, azide, nitrone, and diazocarbonyl derivatives.
  • k′ is the relative rate with benzyl azide set at 1.
  • the second-order rate constant for nitrone 9 was determined by using equimolar mixture of reagents due to a strong absorbance at 305 nm.
  • FIG. 6 illustrates one embodiment of nitrile oxide formation followed by cycloaddition reactions with DIBO (2) for various nitrile oxides.
  • the rate constants and yields for the reactions are listed in Table 1.
  • FIG. 7 is a graphical illustration showing the consumption of DIBO 2 (6 10 ⁇ 5 M in methanol at 25° C.) in the presence of various dipoles (3 mM) for an embodiment of the presently disclosed invention.
  • the lines shown were drawn using parameters obtained by least-squares fitting of single exponential equation.
  • the inset shows reaction of DIBO with 5a at a different time scale.
  • FIG. 8 illustrates one embodiment of one pot oxime and nitrile oxide formation followed by cycloaddition reactions with DIBO (2) for various nitrile oxides.
  • the rate constants and yields for the reactions are listed in Table 2.
  • FIG. 9 is a schematic illustration of an exemplary embodiment of modification of the reducing end of lactose by strain-promoted alkyne-nitrile oxide cycloadditions (SPANOC) employing oxime 14.
  • SPANOC strain-promoted alkyne-nitrile oxide cycloadditions
  • FIG. 10 is an illustration of an embodiment showing labeling and detection of sialic acids on the glycoprotein fetuin using SPANOC.
  • Fetuin samples in lanes 1-4
  • BSA samples in lanes 5-8
  • NaIO 4 samples in lanes 3, 4, 7, and 8
  • the generated C-7 aldehyde was reacted with HONH 2 .HCl to form an oxime, which was oxidized by reacting with BAIB to produce nitrile oxide that was reacted with DIBO derivative 15 (samples in lanes 2, 4, 6, and 8).
  • Incorporated biotin was then detected by Western blot using an antibiotin antibody conjugated to HRP. Total protein loading was confirmed by Coomassie staining.
  • FIG. 11 illustrates exemplary embodiments of selective cycloadditions between galactoside-modified DIBO 19 with either the azide or oxime moiety of linker 18.
  • FIG. 12 is a schematic illustration of an exemplary embodiment of the preparation of a bifunctional compound by a sequential SPAAC and SPANOC.
  • Nitrile oxides could conveniently be prepared by direct oxidation of the corresponding oximes with BAIB, and these conditions made it possible to perform oxime formation, oxidation, and cycloaddition as a one-pot procedure.
  • the methodology was employed to functionalize the anomeric center of carbohydrates with various tags.
  • oximes and azides provide an orthogonal pair of functional groups for sequential metal-free click reactions, and this feature makes it possible to multifunctionalize biomolecules and materials by a simple synthetic procedure that does not require toxic metal catalysts.
  • cyclic alkynes can be used in the methods disclosed herein including, but not limited to, cyclooctynes, monoarylcyclooctynes, and diarylcyclooctynes.
  • Exemplary cyclooctynes include, but are not limited to, those illustrated in FIG. 1 (e.g., monocyclic or bicyclic, unsubstituted or substituted cyclooctynes including, for example, monofluorinated cyclooctynes and difluorinated cyclooctynes). See also, Banert et al., Chem. Comm., 2010, 46(23):4058-4060; Agard et al., J. Am. Chem.
  • Exemplary monoarylcyclooctynes include, but are not limited to those illustrated in FIG. 2 (e.g., monobenzocyclooctynes). See also, Sletten et al., J. Am. Chem. Soc., 2010, 132(33)11799-11805.
  • Exemplary diarylcyclooctynes include, but are not limited to, those listed in FIG. 3 (e.g., dibenzocyclooctynes, aza-dibenzocyclooctynes, and aza-dibenzocyclooctynones). See also, McKay et al., Chem. Comm., 2010, 46(6):931-933; Wong et al., J. Am. Chem. Soc., 1974, 96(17):5604-5605; Kii et al., Organic & Biomolecular Chemistry, 2010, 8(18):4051-4055; Ning et al., Angew.
  • At least one cyclic alkyne includes a diarylcyclooctyne such as a dibenzocyclooctyne.
  • Exemplary dibenzocyclooctynes include those of the formula:
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group (and preferably a C1-C10 organic moiety); each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group (and preferably a C1-C10 organic moiety);
  • X represents C ⁇ O, C ⁇ N—OR 3 , C ⁇ N—NR 3 R 4 , CHOR 3 , CHNHR 3 , BR 3 , NR 3 , O, SiR 3 R 4 , PR 3 , O ⁇ PR 3 or halogen; and each R 3 and R 4 independently represents hydrogen or an organic group (and in some embodiments an organic moiety).
  • each R 1 represents hydrogen and/or each R 2 represents hydrogen.
  • R 3 includes a
  • organic group is used for the purpose of this invention to mean a hydrocarbon group that is classified as an aliphatic group, cyclic group, or combination of aliphatic and cyclic groups (e.g., alkaryl and aralkyl groups).
  • suitable organic groups for compounds of this invention are those that do not interfere with the reaction of an alkyne with a 1,3-dipole-functional compound to form a heterocyclic compound.
  • aliphatic group means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
  • alkyl group means a saturated linear or branched monovalent hydrocarbon group including, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, amyl, heptyl, and the like.
  • alkenyl group means an unsaturated, linear or branched monovalent hydrocarbon group with one or more olefinically unsaturated groups (i.e., carbon-carbon double bonds), such as a vinyl group.
  • alkynyl group means an unsaturated, linear or branched monovalent hydrocarbon group with one or more carbon-carbon triple bonds.
  • cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • alicyclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • aromatic group or “aryl group” means a mono- or polynuclear aromatic hydrocarbon group.
  • heterocyclic group means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulfur, etc.).
  • group and “moiety” are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not so allow for substitution or may not be so substituted.
  • group when the term “group” is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with nonperoxidic O, N, S, Si, or F atoms, for example, in the chain as well as carbonyl groups or other conventional substituents.
  • moiety is used to describe a chemical compound or substituent, only an unsubstituted chemical material is intended to be included.
  • alkyl group is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, tert-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc.
  • alkyl group includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc.
  • the phrase “alkyl moiety” is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, tert-butyl, and the like.
  • Alkynes of Formula I are typically strained, cyclic alkynes. Surprisingly it has been found that alkynes of Formula I as described herein (e.g., wherein X represents C ⁇ O, C ⁇ N—OR 3 , C ⁇ N—NR 3 R 4 , CHOR 3 , or CHNHR 3 ; and each R 3 and R 4 independently represents hydrogen or an organic group) have been found to have higher reactivity towards 1,3-dipole-functional compounds than other strained, cyclic alkynes (e.g., wherein X represents CH 2 ).
  • Density functional theory (B3LYP) calculations of the transition states of cycloadditions of phenyl azide with acetylene and cyclooctyne indicate that the fast rate of the “strain promoted” cycloaddition is actually due to a lower energy required for distorting the 1,3-dipole and alkyne into the transition-state geometry.
  • the first generation of cyclooctynes proceeded with relatively slow rates of reaction; however, it has been found that significant increases in the rate of strain-promoted cycloaddition can be accomplished by appending electron-withdrawing groups to the propargylic position of cyclooctyne (Agard et al., ACS Chem. Biol.
  • difluorinated cyclooctyne (DIFO, 1, FIG. 4 ; Baskin et al., Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16793-16797; Codelli et al., J. Am. Chem. Soc. 2008, 130, 11486-11493) reacts with azides approximately 60 times faster than similar cycloadditions with an unsubstituted cyclooctyne.
  • DIBO 4-dibenzocyclooctynol
  • Exemplary aza-dibenzocyclooctynes include those of the formula:
  • each R 1 independently represents H or an organic group
  • R 2 represents a —C(O)—R 4 group
  • R 4 represents an organic group.
  • each R 1 is hydrogen.
  • Exemplary aza-dibenzocyclooctynones includes those of the formula:
  • each R 1 independently represents H or an organic group
  • R 2 represents an organic group.
  • each R 1 is hydrogen.
  • Exemplary difluorinated cyclooctynes include those of the formula:
  • R 1 represents an organic group
  • Exemplary bicyclo[6.1.0]nonynes include those of the formula:
  • R 1 represents an organic group
  • 1,3-dipole-functional compounds can be used to react with the alkynes disclosed herein.
  • a “1,3-dipole-functional compound” is meant to include compounds having at least one 1,3-dipole group attached thereto.
  • a “1,3-dipole group” is intended to refer to a group having a three-atom pi-electron system containing 4 electrons delocalized over the three atoms.
  • Exemplary 1,3-dipole groups include, but are not limited to, azides, nitrile oxides, nitrones, azoxy groups, and acyl diazo groups.
  • the 1,3-dipole-functional compound can be a biomolecule having at least one 1,3-dipole group attached thereto.
  • the at least one 1,3-dipole-functional compound can include a detectable label (e.g., an immunoassay or affinity label).
  • One or more 1,3-dipole-functional compounds can be combined with an alkyne as described herein under conditions effective to react in a cyclization reaction and form a heterocyclic compound.
  • conditions effective to form the heterocyclic compound can include the substantial absence of added catalyst.
  • Conditions effective to form the heterocyclic compound can also include the presence or absence of a wide variety of solvents including, but not limited to, aqueous (e.g., water) and non-aqueous solvents; protic and aprotic solvents; polar and non-polar solvents; and combinations thereof.
  • the heterocyclic compound can be formed over a wide temperature range, with a temperature range of 0° C. to 40° C. (and in some embodiments 23° C. to 37° C.) being particularly useful when biomolecules are involved. Conveniently, reaction times can be less than one day, and sometimes one hour or even less.
  • Nitrile oxides can undergo cycloadditions with terminal alkynes to give 3,5-isoxazoles (Huisgen, in 1,3- Dipolar Cycloaddition Chemistry ; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 1-176); however, the success of these reactions is often compromised by a slow rate of reaction and competing dimerization of nitrile oxides (Grünanger, in The Chemistry of Heterocyclic Compounds: Isoxazoles ; Taylor, E. C., Weissberger, A., Eds.; Wiley-Interscience: New York, 1991; Part I, Vol. 49, pp 1-416).
  • 3,5-Disubstituted isoxazoles have been prepared in high yield by intramolecular cycloadditions (Nair et al., Tetrahedron 2007, 63, 12247-12275), the use of activated dipolarophiles (König et al., Chem. Ber. 1983, 116, 3580-3590; for example using benzyne, see Crossley et al., Tetrahedron Lett. 2010, 51, 2271-2273; Dubrovskiy et al., Org. Lett. 2010, 12, 1180-1183; Spiteri et al., Org. Biomol. Chem. 2010, 8, 2537-2542; Spiteri et al., Chem. Commun.
  • Second-order rate constants were determined from pseudo first-order rate constants at various concentrations of in situ formed nitrile oxides at 25 ⁇ 0.1° C.
  • c Pseudo first-order kinetics were determined using UV-Vis spectroscopy by following the decay of the absorbance of compound 2 at 305 nm.
  • d [2] 6 ⁇ 10 ⁇ 5 M.
  • DIBO (2) is stable when exposed to BAIB alone, and thus the oxidation and cycloaddition could be performed as a tandem reaction sequence.
  • hydroxylamine decomposes DIBO (2) probably by a nucleophilic attack at the strained alkyne.
  • the success of the transformation required the use of either an equimolar quantity of aldehyde and hydroxylamine or more conveniently the addition of acetone prior to cycloaddition to convert the excess hydroxylamine into ketoxime, which can react with BAIB but does not provide a 1,3-dipole.
  • Rate constants were measured for the tandem sequence of oxidation of oximes to nitrile oxides followed by 1,3-dipolar cycloaddition with 2 establishing that the cycloaddition is the rate-limiting step and highlighting that oxidation with BAIB is exceptionally fast.
  • the rate constant of the reaction was 3.44 M ⁇ 1 s ⁇ 1 , which is almost the same as the value obtained when benzaldehyde imidoyl chloride was employed (3.38M ⁇ 1 s ⁇ 1 .
  • the kinetic data for compounds 6g and 6h demonstrate further that the nature of the substituent has only a small effect on the rate of the reactions.
  • SPANOC can also be used for the installation of tags into sialic acid containing glycoproteins by mild treatment with NaIO 4 to form a C-7 aldehyde, which upon treatment with hydroxylamine will give an oxime that can be oxidized to a nitrile oxide for reaction with derivatives of DIBO.
  • tags can be installed into glycoproteins by stable isoxazoles linkages (Zeng et al., Nat. Methods 2009, 6, 207-209).
  • the glycoprotein fetuin was treated with a 1 mM solution of NaIO 4 for 5 minutes, after which the excess of oxidizing reagent was removed by spin filtration.
  • the resulting aldehyde containing glycoprotein was treated with hydroxylamine to install an oxime, which was immediately oxidized to a nitrile oxide by short treatment with BAIB and then reacted with 15 for 15 minutes to give a biotin containing sialic acid.
  • BSA which does not contain sugar moieties, was subjected to the same sequence of reactions.
  • the presence of biotin was examined by Western blotting using antibiotin antibody conjugated to HRP.
  • fetuin showed strong reaction when subjected to the sequential three-step procedure, whereas BSA was not detected. Furthermore, exclusion of one of the reaction steps abolished detection, confirming the selectivity of the procedure. Quantitative protein and biotin determination indicated that two biotin moieties were installed in each fetuin molecule.
  • the cyclization reaction between the one or more 1,3-dipole-functional compounds and the alkyne can take place within or on the surface of a living cell. Such reactions can take place in vivo or ex vivo.
  • in vivo refers to a reaction that is within the body of a subject.
  • ex vivo refers to a reaction in tissue (e.g., cells) that has been removed, for example, isolated, from the body of a subject.
  • Tissue that can be removed includes, for example, primary cells (e.g., cells that have recently been removed from a subject and are capable of limited growth or maintenance in tissue culture medium), cultured cells (e.g., cells that are capable of extended growth or maintenance in tissue culture medium), and combinations thereof.
  • primary cells e.g., cells that have recently been removed from a subject and are capable of limited growth or maintenance in tissue culture medium
  • cultured cells e.g., cells that are capable of extended growth or maintenance in tissue culture medium
  • An exemplary embodiment of a 1,3-dipole-functional compound is an azide-functional compound of the formula R 8 —N 3 (e.g., represented by the valence structure R 8 - ⁇ N—N ⁇ N + ), wherein R 8 represents and organic group (e.g., a biomolecule).
  • R 8 can include a detectable label (e.g., an affinity label).
  • Cyclization reactions between alkynes as disclosed herein and 1,3-dipole-functional compounds can be used for a wide variety of applications.
  • an alkyne as disclosed herein can be attached to the surface of a substrate.
  • the X group of the alkyne represents a point of attachment to the surface of the substrate.
  • the X group can advantageously be selected to include functionality (e.g., biotin, activated esters, activated carbonates, and the like) to enable attachment of the alkyne to a functional substrate (e.g., amine functionality, thiol functionality, and the like) through a wide variety of reactions.
  • Substrates having an alkyne attached to the surface thereof can be reacted with 1,3-dipole-functional compounds to form heterocyclic compounds, effectively chemically bonding the 1,3-dipole-functional compounds to the substrate.
  • substrates can be, for example, in the form of resins, gels, nanoparticles (e.g., including magnetic nanoparticles), or combinations thereof.
  • such substrates can be in the form of microarrays or even three-dimensional matrices or scaffolds.
  • Exemplary three-dimensional matrices include, but are not limited to, those available under the trade designations ALGIMATRIX 3D Culture system, GELTRIX matrix, and GIBCO three-dimensional scaffolds, all available from Invitrogen (Carlsbad, Calif.). Such three-dimensional matrices can be particularly useful for applications including cell cultures.
  • 1,3-Dipole-functional biomolecules e.g., 1,3-dipole-functional peptides, proteins, glycoproteins, nucleic acids, lipids, saccharides, oligosaccharides, and/or polysaccharides
  • 1,3-Dipole-functional biomolecules can be immobilized on, and preferably covalently attached to, a substrate surface by contacting the 1,3-dipole-functional biomolecules with a substrate having an alkyne attached to the surface thereof under conditions effective for a cyclization reaction to form a heterocyclic compound.
  • conditions effective to form the heterocyclic compound can include the substantial absence of added catalyst.
  • Conditions effective to form the heterocyclic compound can also include the presence or absence of a wide variety of solvents including, but not limited to, aqueous (e.g., water and other biological fluids) and non-aqueous solvents; protic and aprotic solvents; polar and non-polar solvents; and combinations thereof.
  • aqueous e.g., water and other biological fluids
  • non-aqueous solvents e.g., water and other biological fluids
  • protic and aprotic solvents e.g., water and other biological fluids
  • polar and non-polar solvents e.g., polar and non-polar solvents
  • the heterocyclic compound can be formed over a wide temperature range, with a temperature range of 0° C. to 40° C. (and in some embodiments 23° C. to 37° C.) being particularly useful. Conveniently, reaction times can be less than one day, and sometimes one hour or even less.
  • the cyclization reaction can result in an article having a protein immobilized on a three-dimensional matrix.
  • matrices can have a wide variety of uses including, but not limited to, separating and/or immobilizing cell lines.
  • Particularly useful proteins for these applications include, but are not limited to, collagen, fibronectin, gelatin, laminin, vitronectin, and/or other proteins commonly used for cell plating.
  • the novel cycloaddition reaction provided by the invention can be used for labeling of living cells.
  • cells can first be metabolically labeled with an azide-functional precursor to produce azide-functional biomolecules (also referred to as bioconjugates) such as azide-functional glycoproteins (also referred to as glycoconjugates).
  • the cells can then be contacted with an alkyne of Formula I, either in solution or on a substrate as discussed above, under conditions to permit labeling (via the cycloaddition reaction) of the azide-functional biomolecules at the surface of the cell.
  • the resulting triazole conjugate can be detected at the cell surface, or it can be endocytosed by the cell and detected inside the cell.
  • Alkynes of Formula I can also have utility for imaging applications including, for example, as reagents for magnetic resonance imaging (MRI).
  • alkynes of Formula I can contain a fluorescent tag.
  • Alkynes of Formula I can also be useful in qualitative or quantitative proteomics and glycomics applications utilizing mass spectrometry.
  • the alkyne of Formula I can be selected to contain one or more heavy mass isotopes, such as deuterium, 13 C, 15 N, 35 S and the like, and then can be used to label and/or immobilize azide-functional biomolecules as described herein.
  • Alkynes of Formula I can also have utility for applications such as vaccines.
  • alkynes of Formula I can be reacted with an azide-functional protein (e.g., an azide-functional carbohydrate, an azide-functional peptide, and/or an azide-functional glycopeptide), and the resulting triazole conjugate can be used as a carrier protein for the vaccine.
  • an azide-functional protein e.g., an azide-functional carbohydrate, an azide-functional peptide, and/or an azide-functional glycopeptide
  • strain-promoted click reactions can be performed in a sequential manner by tuning the reactivity of 1,3-dipoles or by using a latent 1,3-dipole.
  • the attractiveness of the new approach is that it offers chemical flexibility, avoids toxic metal catalysts, and makes it possible to multifunctionalize compounds by simple chemical manipulations.
  • SPANOC will provide an additional tool for the preparation of increasingly complex materials by simple and flexible chemical manipulations.
  • SPANOC will offer an attractive alternative to the well-established oxime ligation (Dawson et al., Annu. Rev. Biochem. 2000, 69, 923-960; Borgia et al., Trends Biotechnol. 2002, 18, 243-251) because the synthesis of oximes is simple, the isoxazole products are stable, and a combined use with SPAAC will make it possible to introduce two different functional groups.
  • Room temperature refers to ambient room temperature (20-22° C.). Reactions were monitored by Thin Layer Chromatography (TLC) using aluminum backed silica gel 60 (F254) plates, visualized using UV254 nm and potassium permanganate and ninhydrin dips as appropriate. Flash chromatography was carried out routinely using silica gel G60 (SiliCycle, 60-200 ⁇ m 60 ⁇ ) as the stationary phase unless otherwise stated. The NMR spectra were recorded on a Varian Mercury (300 MHz) spectrometer. Chemical shifts are reported in ⁇ units, parts per million (ppm) downfield from TMS.
  • TLC Thin Layer Chromatography
  • Coupling constants are measured in Hertz (Hz) and are unadjusted; therefore, due to limits in resolution, in some cases there are small differences ( ⁇ 1 Hz) in the measured J value of the same coupling constant determined from different signals.
  • Splitting patterns are designed as follows: s—singlet, d—doublet, t—triplet, dd—doublet of doublets, dt—doublet of triplets, td—triplet of doublets, ddd—doublet of doublet of doublets, tt—triplet of triplets, sp—septet, m—multiplet, br—broad.
  • Various 2D techniques and DEPT experiments were used to establish the structures and to assign the signals.
  • High-resolution mass spectra were obtained by using either MALDI-ToF (Applied Biosystems 4700 Proteomics Analyzer) with 2,5-dihydroxybenzoic acid as a matrix or a Sciex API-1 Plus quadrupole mass spectrometer with an electron ionization source.
  • Reverse Phase HPLC purification was performed on an Agilent 1200 series system equipped with an automated injector, UV-detector, fraction-collector and Agilent Zorbax Eclipse XD8-C18 column (5 ⁇ m, 9.4 250 mm). The eluents used for all purifications were: A 0.1% TFA in water; B 0.1% TFA in CH 3 CN, the flow was set to 1.5 ml/min.
  • nitrile oxide derivatives of 5a,b,d-f the imidoyl chlorides 5a-f in methanol (6.0 ⁇ 10 ⁇ 4 to 1.5 ⁇ 10 ⁇ 2 M) were treated with triethylamine and then added to a thermally equilibrated solution of 2, whereas nitrile oxide derivatives of 13a-h were generated by the oxidation of oximes 13a-h using [bis(acetoxy)iodo]benzene. Reactions were monitored by following the decay of the characteristic absorbance of dibenzocyclooctynol 2 at 305 nm.
  • Appropriate fractions were combined and lyophilized to give pure dibenzocyclooctyl-isoxazole 16 and 17, respectively.
  • the nitrile oxide was reacted with DIBO 15 by a copper-free cycloaddition reaction for 30 minutes at room temperature.
  • the samples (25 ⁇ g of protein per lane) were resolved on a 4-20% SDS-PAGE gel (Bio-Rad) and transferred to a nitrocellulose membrane.
  • the membrane was blocked in blocking buffer (nonfat dry milk (5%; Bio-Rad) in PBST (PBS containing 0.1% Tween-20 and 0.1% Triton X-100)) for 2 hours at room temperature.
  • HRP horseradish peroxidase
  • Biotin Quantitation Incorporation of biotin into the protein was quantified using the Fluorescence Biotin Quantitation Kit (Thermo Scientific) according to the manufacturer's protocol. Briefly, the biotinylated protein was dissolved in PBS, and DyLight Reporter (a premix of fluorescent avidin and 40-hydroxyazobenzene-2-carboxylic acid (HABA)) was added to the biotinylated samples and a range of biocytin standards. The avidin in this reporter fluoresces when the weakly interacting HABA is displaced by the biotin. A calibration curve of the biocytin standards was used for calculations. The extent of biotinylation is expressed as moles biotin/mole protein.
  • DyLight Reporter a premix of fluorescent avidin and 40-hydroxyazobenzene-2-carboxylic acid (HABA)
  • Triazole 20 Azide 18 (10 mg, 0.03 mmol) was added to a solution of galactose-DIBO derivative 19 (14.3 mg, 0.03 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 2 hours.
  • Isoxazole 21 A methanolic solution (1 mL) of galactose-DIBO derivative 19 (14.3 mg, 0.03 mmol) was added dropwise to a solution of oxime 18 (12.2 mg, 0.036 mmol) and BAIB (11.6 mg, 0.036 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 10 minutes.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11027260B2 (en) 2019-02-13 2021-06-08 Uchicago Argonne, Llc Low pressure nanowire membrane for catalytic reactions and methods of making and using the same
US11951165B2 (en) 2016-12-30 2024-04-09 Vaxcyte, Inc. Conjugated vaccine carrier proteins
US11998599B2 (en) 2016-12-30 2024-06-04 Vaxcyte, Inc. Polypeptide-antigen conjugates with non-natural amino acids

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9315468B2 (en) 2010-09-27 2016-04-19 University Of Georgia Research Foundation, Inc. Methods including latent 1,3-dipole-functional compounds and materials prepared thereby
GB201300707D0 (en) * 2013-01-15 2013-02-27 Novartis Ag Compounds and processes
EP3097080A1 (de) 2014-01-24 2016-11-30 SynAffix B.V. Verfahren zur cycloaddition einer halogenierten 1,3-dipolverbindung mit einem (hetero)cycloalkyn
WO2015112014A1 (en) * 2014-01-24 2015-07-30 Stichting Katholieke Universiteit Process for the cycloaddition of a hetero(aryl) 1,3-dipole compound with a (hetero)cycloalkyne
WO2015134599A2 (en) * 2014-03-04 2015-09-11 University Of Georgia Research Foundation, Inc. Platinum(iv) compounds and methods of making and using same
EP3129402A4 (de) 2014-04-08 2017-12-13 University Of Georgia Research Foundation, Inc. Ortsspezifische antikörper-wirkstoff-glykokonjugate und verfahren
WO2020028110A1 (en) * 2018-07-30 2020-02-06 Siemens Healthcare Diagnostics Inc. Kits, microfluidics devices, and methods for performing biotin assays

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030165561A1 (en) 2001-11-02 2003-09-04 Rajinder Singh Substituted diphenyl heterocycles useful for treating HCV infection
US20050143583A1 (en) 2001-10-12 2005-06-30 Onconova Therapeutics, Inc. Processes for the preparation of substituted isoxazoles and 2-isoxazolines
WO2009053339A2 (en) 2007-10-22 2009-04-30 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Cholesterol derivatives of inhibitors of viral fusion
WO2009067663A1 (en) 2007-11-21 2009-05-28 University Of Georgia Research Foundation, Inc. Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
US20100210854A1 (en) 2009-02-19 2010-08-19 Popik Vladimir V Cyclopropenones and the Photochemical Generation of Cyclic Alkynes Therefrom
WO2012047663A2 (en) 2010-09-27 2012-04-12 University Of Georgia Reaserch Foundation, Inc. Methods including latent 1,3-dipole-functional compounds and materials prepared thereby

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050143583A1 (en) 2001-10-12 2005-06-30 Onconova Therapeutics, Inc. Processes for the preparation of substituted isoxazoles and 2-isoxazolines
US20030165561A1 (en) 2001-11-02 2003-09-04 Rajinder Singh Substituted diphenyl heterocycles useful for treating HCV infection
US6759538B2 (en) * 2001-11-02 2004-07-06 Rigel Pharmaceuticals, Inc. Substituted diphenyl heterocycles useful for treating HCV infection
WO2009053339A2 (en) 2007-10-22 2009-04-30 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Cholesterol derivatives of inhibitors of viral fusion
WO2009067663A1 (en) 2007-11-21 2009-05-28 University Of Georgia Research Foundation, Inc. Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
US8133515B2 (en) * 2007-11-21 2012-03-13 University Of Georgia Research Foundation, Inc. Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
US8940859B2 (en) * 2007-11-21 2015-01-27 University Of Georgia Research Foundation, Inc. Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
US20150126706A1 (en) 2007-11-21 2015-05-07 University Of Georgia Research Foundation, Inc. Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
US20100210854A1 (en) 2009-02-19 2010-08-19 Popik Vladimir V Cyclopropenones and the Photochemical Generation of Cyclic Alkynes Therefrom
US8258347B2 (en) * 2009-02-19 2012-09-04 University Of Georgia Research Foundation, Inc. Cyclopropenones and the photochemical generation of cyclic alkynes therefrom
WO2012047663A2 (en) 2010-09-27 2012-04-12 University Of Georgia Reaserch Foundation, Inc. Methods including latent 1,3-dipole-functional compounds and materials prepared thereby

Non-Patent Citations (156)

* Cited by examiner, † Cited by third party
Title
Agard et al., "A comparative study of bioorthogonal reactions with azides" Acs Chemical Biology, 2006; 1(10):644-8.
Agard et al., "A strain-promoted [3+2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems" J. Am. Chem. Soc., 2004; 126(46):15046-7.
Aucagne et al., "Chemoselective formation of successive triazole linkages in one pot: "click-click" chemistry" Org. Lett. 2006; 8(20), 4505-7.
Bach, "Ring strain energy in the cyclooctyl system. The effect of strain energy on [3+2] cycloaddition reactions with azides" J. Am. Chem. Soc., Apr. 15, 2009;131(14): 5233-43.
Baldoli et al., "Coumarin as Dipolarophile towards 3,5-Dichloro-2,4,6-trimethylbenzonitrile Oxide" J. Heterocycl. Chem. 1994, 31, 251-253.
Banert et al., "Elusive ethynyl azides: trapping by 1,3-dipolar cycloaddition and decomposition to cyanocarbenes" Chem. Comm., 2010, 46(23):4058-4060.
Bantscheff et al., "Quantitative mass spectrometry in proteomics: a critical review" Anal. Bioanal. Chem. 2007; 389(4):1017-31.
Baskin et al., "Bioorthogonal Click Chemistry: Covalent Labeling in Living Systems" QSAR Comb. Sci., 2007; 26:1211-9.
Baskin et al., "Copper-free click chemistry for dynamic in vivo imaging" Proc. Natl. Acad. Sci. USA 2007; 104:16793-7.
Becer et al., "Click chemistry beyond metal-catalyzed cycloaddition" Angew. Chem. Int. Ed. Engl., 2009; 48(27):4900-8.
Bernardin et al., "Copper-Free Click Chemistry for Highly Luminescent Quantum Dot Conjugates: Application to in Vivo Metabolic Imaging" Bioconjugate Chem., Apr. 21, 2010; 21(4):583-8.
Binder et al., "Click chemistry in polymer and material science: An update" Macromol. Rapid Commun. 2008; 29:952-81.
Boons, Geert-Jan "Synthesis/Immunological Properties of Lewis Antigens" Grant Abstract, Grant No. 1RO1 CA88986-01A2 [online]. U.S. National Institutes of Health, project dates Jul. 15, 2002 to Jun. 30, 2006 [retrieved on Jul. 14, 2015]. Retrieved from the Internet:; 2 pgs.
Boons, Geert-Jan "Synthesis/Immunological Properties of Lewis Antigens" Grant Abstract, Grant No. 1RO1 CA88986-01A2 [online]. U.S. National Institutes of Health, project dates Jul. 15, 2002 to Jun. 30, 2006 [retrieved on Jul. 14, 2015]. Retrieved from the Internet:< projectreporter.nih.gov >; 2 pgs.
Borgia et al., "Chemical synthesis of proteins" Trends Biotechnol. 2002, 18, 243-251.
Böttcher et al., "Showdomycin as a versatile chemical tool for the detection of pathogenesis-associated enzymes in bacteria" J Am Chem Soc, May 26, 2010; 132(20):6964-72.
Brand et al., "Nitrosation of sugar oximes: preparation of 2-glycosyl-1-hydroxydiazene-2-oxides" Chem.-Eur. J. 2006, 12, 499-509.
Burrows et al., "Oxidative Nucleobase Modifications Leading to Strand Scission" Chem. Rev., 1998; 98(3):1109-52.
Carrico et al., "Introducing genetically encoded aldehydes into proteins" Nat. Chem. Biol. 2007, 3, 321-2.
Chaffins et al., "An Efficient Synthesis of Dibenzocycloocta-4a,6a,-diene-5,11-diyne and its Precursors" Synthesis, 2002; 9:1191-4.
Chang et al., "Copper-free click chemistry in living animals" Proc. Nat. Acad. Sci., Feb. 2, 2010; 107(5):1821-6.
Chenoweth et al., "Cyclooctyne-based reagents for uncatalyzed click chemistry: A computational survey" Org. Biomol. Chem., Dec. 21, 2009; 7(24):5255-8. Epub Nov. 9, 2009.
Chin et al., "An expanded eukaryotic genetic code" Science 2003; 301(5635):964-7.
Choi et al., "Surface Modification of Functional Nanoparticles for Controlled Drug Delivery" J. Dispersion Sci. Tech. 2003; 24(3-4):475-87.
Clark et al., "Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 1. Synthesis of cyclic amines" Chem. Soc. Perkin Trans. 2001; 1:3312-24.
Codelli et al., "Second-generation difluorinated cyclooctynes for copper-free click chemistry" J. Am. Chem. Soc., 2008, 130(34)11486-11493.
Crossley et al., "Cycloaddition of benzynes and nitrile oxides: synthesis of benzisoxazoles" Tetrahedron Lett. 2010, 51, 2271-2273.
Das et al., "Hypervalent iodine-mediated interaction of aldoximes with activated alkenes including Baylis-Hillman adducts: a new and efficient method for the preparation of nitrile oxides from aldoximes" Tetrahedon Lett. 2004, 45, 7347-7350.
Dawson et al., "Synthesis of native proteins by chemical ligation" Annu. Rev. Biochem. 2000, 69, 923-960.
Debets et al., "Aza-dibenzocyclooctynes for fast and efficient enzyme PEGylation via copper-free (3+2) cycloaddition" Chem. Comm., 2010, 46(1):97-99.
Debets et al., "Azide: a unique dipole for metal-free bioorthogonal ligations" ChemBioChem, Jun. 14, 2010; 11(9):1168-84.
Dedola et al., "Recent applications of the Cu(I)-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry" Org. Biomol. Chem. 2007; 5(7):1006-17.
Dicken et al., "Reactions at High Pressures. [3+2] Dipolar Cycloaddition of Nitrones with Vinyl Ethers" J. Org. Chem. 1982; 47:2047-51.
Dommerholt et al., "Readily Accessible Bicyclononynes for Bioorthogonal Labeling and Three-Dimensional Imaging of Living Cells" Angew. Chemie-International Ed., 2010, 49(49):9422-9425.
Dommerholt et al., "Readily Accessible Bicyclononynes for Bioorthogonal Labeling and Three-Dimensional Imaging of Living Cells" Supporting Information, Angew. Chemie-International Ed., 2010, 49(49): 22 pages.
Dubrovskiy et al., "Synthesis of benzisoxazoles by the [3+2] cycloaddition of in situ generated nitrile oxides and arynes" Org. Lett. 2010, 12, 1180-1183.
Ebisu et al., "N-terminal specific point-immobilization of active proteins by the one-pot NEXT-A method" ChemBioChem, Oct. 12, 2009; 10(15):2460-64.
Ess et al., "Transition states of strain-promoted metal-free click chemistry: 1,3-dipolar cycloadditions of phenyl azide and cyclooctynes" Org. Lett., Apr. 17, 2008; 10(8):1633-6. Epub Mar. 26, 2008.
European Patent Application No. 11 83 1305.5, filed Apr. 24, 2013; Extended European Search Report, issued Mar. 5, 2014; 7 pages.
Fernandez-Suarez et al., "Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes" Nat. Biotechnol., 2007; 25(12):1483-7.
Fleischmann et al., "Modification of Polymer Surfaces by Click Chemistry" Macromol. Rapid. Commun., 2008; 29:1177-85.
Fournier et al., "Clicking polymers: a straightforward approach to novel macromolecular architectures" Chem Soc. Rev., 2007; 36(8):1369-80.
Gaetke et al., "Copper toxicity, oxidative stress, and antioxidant nutrients" Toxicology, 2003; 189(1-2):147-63.
Gaucher et al., "Block copolymer micelles: preparation, characterization and application in drug delivery" J. Control. Release 2005; 109(1-3):169-88.
Gierlich et al., "Click Chemistry as a Reliable Method for the High-Density Postsynthetic Functionalization of Alkyne-Modified DNA" Org. Lett., 2006; 8(17):3639-42.
Gilmore et al., "N-terminal protein modification through a biomimetic transamination reaction" Angew. Chem., Int. Ed. Aug. 11, 2006; 45(32):5307-11.
Gramlich et al., "Postsynthetic DNA Modification through the Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction" Angew. Chem. Int. Ed. Engl., 2008; 47(44):8350-8.
Green, "Avidin and streptavidin" Methods Enzymol. 1990; 184:51-67.
Grünanger, in The Chemistry of Heterocyclic Compounds: Isoxazoles; Taylor, E. C., Weissberger, A., Eds.; Wiley-Interscience: New York, 1991; Part I, vol. 49, Cover Page, Title Page and Table of Contents, 13 pages.
Grundmann et al., "Nitrile oxides. XII. Cycloaliphatic and aliphatic stable nitrile oxides" J. Org. Chem. 1969, 34(6), 2016-2018.
Grundmann, "Methoden der organischen Chemie (Houben-Weyl-Muller)" 1965, Stuttgart, XP055168227, pp. 846-847.
Gutsmiedl et al., "Copper-free "click" modification of DNA via nitrile oxide-norbornene 1,3-dipolar cycloaddition" Org. Lett. Jun. 4, 2009 11(11), 2405-8.
Hahn, Michael "A Toolkit for in Vivo Visualization/Modulation of Plant Cell Wall Polysaccharides" Grant Abstract, Grant No. IOS-0923992 [online]. National Science Foundation, project dates Mar. 1, 2010 to Feb. 29, 2016 (Estimated) [retrieved on Jul. 14, 2015]. Retrieved from the Internet:; 2 pgs.
Hahn, Michael "A Toolkit for in Vivo Visualization/Modulation of Plant Cell Wall Polysaccharides" Grant Abstract, Grant No. IOS-0923992 [online]. National Science Foundation, project dates Mar. 1, 2010 to Feb. 29, 2016 (Estimated) [retrieved on Jul. 14, 2015]. Retrieved from the Internet:<nsf.gov/awardsearch>; 2 pgs.
Hansen et al., "One-pot copper(I)-catalyzed synthesis of 3,5-disubstituted isoxazoles" J. Org. Chem. Sep. 16, 2005, 70(19):7761-4.
Hanson et al., "Tailored glycoproteomics and glycan site mapping using saccharide-selective bioorthogonal probes" J. Am. Chem. Soc. 2007;129(23):7266-7.
He et al., "1,3-Dipolar cycloaddition of diazoacetate compounds to terminal alkynes promoted by Zn(OTf)2: an efficient way to the preparation of pyrazoles" Tetrahedron Lett. 2009, 50, 2443-2445.
Hein et al., "Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides" Chem. Soc. Rev., Apr. 2010; 39(4):1302-15.
Huisgen, "1,3-Dipolar Cycloaddition Chemistry" Padwa, A., Ed.; Wiley: New York, 1984; vol. 1, Cover page, title page and table of contents (5 pages).
Iehl et al., "Sequential copper catalyzed alkyne-azide and thiol-ene click reactions for the multiple functionalization of fullerene hexaadducts" Chem. Commun. Jun. 2010; 46(23):4160-4162. Epub May 10, 2010.
Iha et al., "Applications of Orthogonal "Click" Chemistries in the Synthesis of Functional Soft Materials" Chem. Rev., 2009; 109(11):5620-86.
Im et al., "Patterning Nanodomains with Orthogonal Functionalities: Solventless Synthesis of Self-Sorting Surfaces" J. Am. Chem. Soc., 2008; 130(44):14424-5.
Inouye et al., "The Configurations of N-Methyl- and N-t-Butyl-alpha-methoxycarbonlmethanimine N-Oxides" Bull. Chem. Soc. Jpn. 1983; 56:3541-2.
Inouye et al., "The Configurations of N-Methyl- and N-t-Butyl-α-methoxycarbonlmethanimine N-Oxides" Bull. Chem. Soc. Jpn. 1983; 56:3541-2.
International Patent Application No. PCT/US2011/053487, filed Sep. 27, 2011; International Preliminary Report on Patentability issued Apr. 11, 2013; 8 pages.
International Patent Application No. PCT/US2011/053487, filed Sep. 27, 2011; International Search Report and Written Opinion issued Apr. 9, 2012; 12 pages.
Isobe et al., "Triazole-linked analogue of deoxyribonucleic acid ((TL)DNA): design, synthesis, and double-strand formation with natural DNA" Org. Lett. 2008; 10(17): 3729-3732. Epub Jul. 26, 2008.
Jacobs et al., "Systems analysis of protein modification and cellular responses induced by electrophile stress" Acc Chem Res May 18, 2010; 43(5):673-83.
Jewett et al., "Cu-free click cycloaddition reactions in chemical biology" Chem. Soc. Rev. Apr. 2010; 39(4):1272-9.
Jewett et al., "Rapid Cu-free click chemistry with readily synthesized biarylazacyclooctynones" J. Am. Chem. Soc., Mar. 24, 2010; 132(11):3688-90.
Jin et al., "An efficient, facile, and general synthesis of 1h-indazoles by 1,3-dipolar cycloaddition of arynes with diazomethane derivatives" Angew. Chem., Int. Ed. Engl. 2007; 46(18):3323-5.
Johnson et al., "Copper-free click chemistry for the in situ crosslinking of photodegradable star polymers" Chem. Commun. 2008, (26):3064-6.
Jung et al., "Direct synthesis of dibenzocyclooctadienes via double ortho Friedel-Crafts alkylation by the use of aldehyde-trimethylsilyl iodide adducts" J. Org. Chem. 1978; 43(19):3698-701.
Jung et al., "Total synthesis of isopavine and intermediates for the preparation of substituted amitriptyline analogs: facile routes to substituted dibenzocyclooctatrienes and dibenzocycloheptatrienes" J. Am. Chem. Soc. 1981; 103(8):1984-92.
Kaffy et al., "1,3-Dipolar cycloaddition route to novel isoxazole-type derivatives related to combretastatin A-4" Elsevier, Tetrahedon Letters, 2004; 45:3359-62.
Kele et al., "Dual labeling of biomolecules by using click chemistry: a sequential approach" Angew. Chem. Int. Ed. Engl., 2009; 48(2):344-7.
Kho et al., "A tagging-via-substrate technology for detection and proteomics of farnesylated proteins" Proc. Natl. Acad. Sci. USA 2004, 101(34):12479-84.
Kiessling et al., "Chemical approaches to glycobiology" Annu. Rev. Biochem. 2010; 79: 619-53.
Kii et al., "Strain-promoted double-click reaction for chemical modification of azido-biomolecules" Org Biomol Chem, Sep. 21, 2010; 8(18):4051-5.
Kolb et al., "The growing impact of click chemistry on drug discovery" Drug Discovery Today 2003; 8(24):1128-37.
König et al., "1,3-Dipolare Cycloadditionen bei Cycloalkeninen" Chem. Ber. 1983; 116, 3580-3590.
Ku et al., "Surface Patterning with Fluorescent Molecules Using Click Chemistry Directed by Scanning Electrochemical Microscopy" J. Am. Chem Soc., 2008; 130(8):2392-3.
Kuijpers et al., , B. H. M.; Groothuys, S.; Org. Process Res. Dev. 2008, 12, 503-511.
Lallana et al., "Surpassing the use of copper in the click functionalization of polymeric nanostructures: a strain-promoted approach" J. Am. Chem. Soc., 2009, 131(16):5748-50.
Landi et al., "Synthesis and application of a new cleavable linker for "click"-based affinity chromatography" Org Biomol Chem. Jan. 7, 2010; 8(1):56-9. Epub Oct. 13, 2009.
Lau et al., "Capture and analysis of quantitative proteomic data" Proteomics 2007; 7(16):2787-99.
Laughlin et al., "In Vivo Imaging of Membrane-Associated Glycans in Developing Zebrafish" Science, 2008; 320(5876):664-7.
Laurent et al., "Glycoarrays-tools for determining protein-carbohydrate interactions and glycoenzyme specificity" Chem. Commun (Camb), Oct. 7, 2008; (37), 4400-12. Epub Aug. 5, 2008.
Lavasanifar et al., "Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery" Adv. Drug Delivery Rev. 2002; 54(2):169-90.
Ledin et al., "Convergent assembly and surface modification of multifunctional dendrimers by three consecutive click reactions" Chemistry, 2011; 17(3): 839-46. Epub Nov. 17, 2010.
Lee et al., "An efficient and practical method for the synthesis of mono-N-protected a,w-diaminoalkanes" Tetrahedron Lett. 2001; 42:2709-11.
Link et al., "Cell surface labeling of Escherichia coli via copper(I)-catalyzed [3+2] cycloaddition" J. Am. Chem. Soc. 2003; 125(37):11164-5.
Link et al., "Discovery of aminoacyl-tRNA synthetase activity through cell-surface display of noncanonical amino acids" Proc. Natl. Acad. Sci. USA, 2006; 103(27): 10180-5.
Liu et al., "A Particularly Convenient Preparation of Benzohydroximinoyl Chlorides (Nitrile Oxide Precursors)" J. Org. Chem. 1980, 45, 3916-3918.
Liu et al., "Synthesis of indazoles by the [3+2] cycloaddition of diazo compounds with arynes and subsequent acyl migration" J. Org. Chem. 2008; 73(1):219-26. Epub Dec. 8, 2007.
Luchansky et al., "Azido sialic acids can modulate cell-surface interactions" ChemBioChem 2004; 5(12):1706-9.
Mader et al., "Surface-modified upconverting microparticles and nanoparticles for use in click chemistries" Chemistry, May 10, 2010; 16(18):5416-24.
Mamidyala et al., "In situ click chemistry: probing the binding landscapes of biological molecules" Chem. Soc. Rev., Apr. 2010; 39(4):1252-61.
McKay et al., "Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions with cycloctynes" Chem. Commun. 2010; 46:931-3.
Meldal et al., "Cu-catalyzed azide-alkyne cycloaddition" Chem. Rev. Aug. 2008; 108(8):2952-3015.
Mendelsohn et al., "Oxidation of oximes to nitrile oxides with hypervalent iodine reagents" Org. Lett. Apr. 2, 2009; 11(7):1539-42.
Michel et al., "Carbohydrate Microarrays by Microcontact "Click" Chemistry" Langmuir, 2008; 24(21):12116-8.
Moses et al., "The growing applications of click chemistry" Chem. Soc. Rev. 2007; 36(8):1249-62.
Nair et al., "Intramolecular 1,3-dipolar cycloaddtion reactions in targeted syntheses" Tetrahedron, 2007; 63, 12247-75.
Nandivada et al., "Click Chemistry: Versatility and Control in the Hands of Materials Scientists" Adv. Mater. 2007; 19(17):2197-2208.
Nebhani et al., "Orthogonal Transformations on Solid Substrates: Efficient Avenues to Surface Modification" Adv. Mat., 2009; 21(34):3442-68.
Neef et al., "Selective fluorescence labeling of lipids in living cells" Angew. Chem. Int. Ed., 2009, 48(8):1498-500.
Nessen et al., "Selective enrichment of azide-containing peptides from complex mixtures" J. Proteome Res., 2009; 8(7):3702-11.
Ning et al., "Protein Modification by Strain-Promoted Alkyne-Nitrone Cycloaddition" Agnew Chem. Int. Ed. 2010; 49:3065-68.
Ning et al., "Visualizing metabolically labeled glycoconjugates of living cells by copper-free and fast huisgen cycloadditions" Angew. Chem-Int Ed. Engl, 2008; 47(12):2253-5.
Nishiyama et al., "Nanostructured devices based on block copolymer assemblies for drug delivery: designing structures for enhanced drug function" Adv. Polym. Sci. 2006; 193:67-101.
Nurmi et al., "Glycopolymers via catalytic chain transfer polymerisation (CCTP), Huisgens cycloaddition and thiol-ene double click reactions" Chem. Commun.(Camb), May 21, 2009; (19):2727-9.
Ochiai et al., "Expeditious Chemoenzymatic Synthesis of Homogenous N-Glycoproteins Carrying Defined Oligosaccharide Ligands" J. Am. Chem. Soc., 2008; 130(41):13790-803.
Ohtsubo et al., "Glycosylation in cellular mechanisms of health and disease" Cell Sep. 8, 2006; 126(5):855-67.
Ornelas et al., "Strain-promoted alkyne azide cycloaddition for the functionalization of poly(amide)-based dendrons and dendrimers" J. Am. Chem. Soc., Mar. 24, 2010; 132(11):3923-31.
Orski et al., "High density orthogonal surface immobilization via photoactivated copper-free click chemistry" J. Am. Chem. Soc., Aug. 18, 2010; 132(32):11024-26.
Paulson et al., "Sweet spots in functional glycomics" Nat. Chem. Biol. May 2006; 2(5):238-48.
Poloukhtine et al., "Selective labeling of living cells by a photo-triggered click reaction" J. Am. Chem. Soc., Nov. 4, 2009; 131(43):15769-76.
Popik, Vladimir "Career: Towards Space- and Time-resolved Generation of p-Benzyne Diradical: development of Photoswitchable Analogs of Natural Enediyne Antibiotics" Grant Abstract, Grant No. CHE-0449478 [online]. National Science Foundation, project dates Jan. 1, 2005 to Jun. 30, 2006 (Estimated) [retrieved on Jul. 14, 2015]. Retrieved from the Internet:; 2 pgs.
Popik, Vladimir "Career: Towards Space- and Time-resolved Generation of p-Benzyne Diradical: development of Photoswitchable Analogs of Natural Enediyne Antibiotics" Grant Abstract, Grant No. CHE-0449478 [online]. National Science Foundation, project dates Jan. 1, 2005 to Jun. 30, 2006 (Estimated) [retrieved on Jul. 14, 2015]. Retrieved from the Internet:<nsf.gov/awardsearch>; 2 pgs.
Prescher et al. "Chemistry in Living Systems" Nat. Chem. Biol. 2005; 1(1):13-21.
Qi et al., "Copper-promoted cycloaddition of diazocarbonyl compounds and acetylides" Angew. Chem. Int. Ed. Engl. 2007; 46(18):3242-4.
Ramón et al., "Au/Ag-cocatalyzed aldoximes to amides rearrangement under solvent-and acid-free conditions" J. Org. Chem. Feb. 19, 2010; 75(4):1197-202.
Ratner et al., Biomaterials science: an introduction to materials in medicine, Academic Press: San Diego, California; 2004. Cover page, title page and table of contents; 8 pages.
Rösler et al., "Advanced drug delivery devices via self-assembly of amphiphilic block copolymers" Adv. Drug Delivery Rev. 2001; 53(1):95-108.
Rostovtsev et al., "A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes" Angew. Chem., Int. Ed. Engl. 2002; 114(14):2708-11.
Sanders et al., "Metal-Free Sequential [3+2] Dipolar Cycloadditions using Cycloctynes and 1,3-Dipoles of Different Reactivity" Journal of the Amer. Chem. Society, 2011; 133: 949-57.
Schoenebeck et al., "Reactivity and regioselectivity in 1,3-dipolar cycloadditions of azides to strained alkynes and alkenes: a computational study" J. Am. Chem. Soc., 2009; 131(23):8121-33.
Schwabacher et al., "Desymmetrization Reactions: Efficient Preparation of Unsymmetrically Substituted Linker Molecules" J. Org. Chem. 1998; 63(5):1727-9.
Seitz et al., "5,6-Didehydro-11,12-dihydrodibenzo[a,e]-cyclootene" Angew. Chem., Int. Ed., 1969; 8(6):447-8.
Sivakumar et al., "A fluorogenic 1,3-dipolar cycloaddition reaction of 3-azidocoumarins and acetylenes" Org. Lett. 2004; 6(24):4603-6.
Sletten et al., "A hydrophilic azacyclooctyne for Cu-free click chemistry" Organic Letters, Jul. 17, 2008; 10(14):3097-9.
Sletten et al., "Difluorobenzocyclooctyne: synthesis, reactivity, and stabilization by beta-cyclodextrin" J. Am. Chem. Soc., Aug. 25, 2010; 132(33):11799-805.
Speers et al., "Activity-Based Protein Profiling in Vivo Using a Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition" J. Am. Chem. Soc., 2003; 125(16):4686-7.
Spiteri et al., "An efficient entry to 1,2-benzisoxazoles via 1,3-dipolar cycloaddition of in situ generated nitrile oxides and benzyne" Org. Biomol. Chem. Jun. 7, 2010; 8(11):2537-42.
Spiteri et al., "An improved synthesis of 1,2-benzisoxazoles: TBAF mediated 1,3-dipolar cycloaddition of nitrile oxides and benzyne" Chem. Commun. 2010; 46(8):1272-4. Epub Jan. 11, 2010.
Stockmann et al., "Development and evaluation of new cyclooctynes for cell surface glycan imaging in cancer cells" Chemical ScienceMay 2011; 2(5):932-6.
Sun et al., "Carbohydrate and Protein Immobilization onto Solid Surfaces by Sequential Diels-Alder and Azide-Alkyne Cycloadditions" Bioconjugate Chem., 2006; 17(1):52-7.
Tanrikulu et al., "Discovery of Escherichia coli methionyl-tRNA synthetase mutants for efficient labeling of proteins with azidonorleucine in vivo" Proc. Natl. Acad. Sci. USA, 2009; 106(36), 15285-90.
Tao, "Soluble polymer-based isotopic labeling (SoPIL): a new strategy to discover protein biomarkers?" Expert Rev. Proteomics 2007; 4(5):603-7.
Tornøe et al., "Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides" J. Org. Chem. May 3, 2002; 67(9):3057-64.
Turner et al., "Heats of hydrogenation. IX. Cyclic acetylenes and some miscellaneous olefins" J. Am. Chem. Soc. 1973; 95(3):790-2.
Valverde et al., "Click á la carte: robust semi-orthogonal alkyne protecting groups for multiple successive azide/alkyne cycloadditions" Tetrahedron, 2009; 65, 7597-602.
van Berkel et al., "Metal-free triazole formation as a tool for bioconjugation" ChemBioChem 2007; 8(13):1504-8.
von Wittig et al., "Reaktionen von Cyclooctin mit einigen Carbenoiden und Carben-Vorläufern" Liebigs Ann. Chem. 1970, 741, 79-88.
Wang et al., "Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition" J. Am. Chem. Soc., 2003; 125(11):3192-3.
Weisbrod et al., "Novel strategies for the site-specific covalent labelling of nucleic acids" Chem. Commun., 2008; (44):5675-85.
Wilchek et al., "Introduction to avidin-biotin technology" Methods Enzymol. 1990; 184:5-13.
Wilson et al., "Noncovalent cell surface engineering with cationic graft copolymers" J. Am. Chem. Soc. Dec. 30, 2009; 131(51):18228-9.
Wittig et al., "Zur Existenz Niedergliedriger Cycloalkine, I" A. Chem. Ber. 1961; 94, 3260-75.
Wong et al., "Selective Covalent Protein Immobilization: Strategies and Applications" Chem. Rev., 2009; 109(9):4025-53.
Wong et al., Communications to the Editor: "Synthesis of sym-Dibenzo-1,5-cyclooctadiene-3,7-diyne and sym-Dibenzo-1,3,5-cyclooctatrien-7-yne, Presumably Planar Conjugated Eight-Membered Ring Compounds" J. Am. Chem. Soc., 1974, 96(17):5604-5.
Wu et al., "Catalytic Azide-Alkyne Cycleaddition: Reactivity and Applications" Aldrichimica Acta, 2007; 40:7-17.
Zeng et al., "High-efficiency labeling of sialylated glycoproteins on living cells" Nat. Methods, Mar. 2009; 6(3):207-9.
Zhang et al., "Bioconjugated Janus Particles Prepared by in Situ Click Chemistry" Chem. Meter. Aug. 7, 2009; 21(17):4012-8.
Zou et al., "Cu-free cycloaddition for identifying catalytic active adenylation domains of nonribosomal peptide synthetases by phage display" Bioorg. Med. Chem. Lett., 2008; 18(20):5664-7.

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